The comorbidity between major depressive disorder (MDD) and obesity appears especially strong in and perhaps limited to females, even controlling for demographic variables, as evidenced by epidemiological and behavioral studies. Further, obese patients with MDD demonstrate worse treatment outcomes compared to healthy-weight counterparts. Given the significant health burden associated with these comorbid disturbances of emotion regulation and food intake, it is important to better characterize the identified but understudied relationship between MDD and obesity. The purpose of this Mentored Research Scientist Development Plan is to assist the candidate in achieving the following goals: a) gain experience in clinical symptomatology and psychiatric treatment of mood disorders, b) develop a knowledge base in the neuroendocrine system, integral to the study of mood disorders and abnormal food motivation, c) obtain expert training in advanced modeling of fMRI data, d) enhance her understanding of critical hormone and neuropeptide signaling in discrete hypothalamic nuclei, all while e) continuing to expand her skills in the field of sex differences in the brain in psychiatric disorders. Under the strong mentorship of Dr. Jill Goldstein [an expert on sex differences in the brain and the role of hormones in psychiatric disorders at Brigham and Women's Hospital (BWH)], Dr. Anne Klibanski [an expert in neuroendocrinology at Massachusetts General Hospital (MGH)], Dr. David Silbersweig (an expert in neuropsychiatry in MDD at BWH), Dr. Laura Miller (an expert in women's mental health at BWH) and Dr. Susan Whitfield-Gabrieli (a mathematician at Massachusetts Institute of Technology with expertise in advanced fMRI methodology), the candidate will develop requisite skills to gain independence in the study of mood disturbances and abnormal food motivation using an interdisciplinary approach combining functional neuroimaging and neuroendocrine techniques. The research plan aims to 1) delineate, using fMRI, potential differences in brain activation patterns in regions implicated in food reward in obese women with MDD compared with healthy-weight women with MDD, healthy-weight women without MDD, and obese women without MDD;2) identify relationships between brain activation in subcortical regions of interest and HPA- /HPG-axis hormones and appetite-regulatory peptides in women with MDD and obesity;and 3) test hypotheses regarding associations between MDD symptoms and a) HPA-/HPG-axis hormones and appetite-regulatory peptides, and b) food reward circuitry functioning, in women with MDD and obesity. The candidate's long term goal is to collaborate with treatment specialists to use these techniques and the knowledge gained from these initial studies to design prevention, prediction, and treatment efficacy studies. Facilities provided through the BWH Departments of Psychiatry and Radiology and Division of Women's Health, MGH Martinos Center for Biomedical Imaging, and Harvard Clinical and Translational Science Center, offer the candidate a world-class environment in which to execute her career development plan activities and proposed research. PUBLIC HEALTH RELEVANCE: Women are at a higher risk of developing major depressive disorder and obesity, the co-occurrence of which is associated with poor treatment outcomes. This project will better characterize the identified but understudied relationship between depression and obesity by examining abnormalities in brain regions related to food reward and hormones that regulate mood and appetite in women with depression and obesity. Understanding the shared brain and hormonal pathways that lead to depression and obesity in women will provide a basis for the development of sex-specific preventative approaches to treatment and ease the disease burden associated with this comorbid condition.